Michael reaction support

The Michael reaction involving addition to carbon-carbon double bonds containing an electron-withdrawing group is catalysed by base. A variety of heterogeneous bases which can be reused are known, including alumina, KF on alumina and phenolates supported on silica, the last having proved particularly effective for addition of /3-keto esters to enones (Scheme 1.7). 

Bis(indolyl)nitroethanes are obtained readily in 7-10 min in high yields (70-86%) on fine TLC-grade silica gel (5-40 pm) by Michael reaction of 3-(2 -nitrovinyl) indole with indoles. The same reaction reported requires 8-14 h for completion at room temperature [77]. Several functionalized resins have been prepared from Merrifield resin via a MW-assisted procedure that utilized mixed solvent system to facilitate the swelling of resins and coupling with microwaves [78], These resins can function as solid supports or polymeric scavengers in solid phase synthesis. 

Ishikawa and co-workers also reported a class of structurally modified guanidines for promotion of the asymmetric Michael reaction of ierf-butyl-diphenylimino-acetate to ethyl acrylate [124,125]. In addition to a polymer support design (Scheme 69), an optical resolution was developed to achieve chiral 1,2-substituted ethylene-l,2-di-amines, a new chiral framework for guanidine catalysis. The authors discovered that incorporating steric bulk and aryl substituents in the catalyst did improve stereoselec-tivitity, although the reactivity did suffer (Scheme 70, Table 4). 

Soon thereafter, the Yamamoto group reported an extension of this work to the highly diastereo- and enantioselective synthesis of nitroso Diels-Alder-type bicycloketones using dienamines in the presence of the BINOL derivative 44 (Scheme 5.61) [115]. This reaction was thought to proceed through a sequential N-NA/ hetero-Michael reaction mechanism. Support for this mechanism was provided from an experiment employing bulkyl 4,4-diphenyl dienamine where the N-NA... 

Arylsulfonylmethyl-substituted dinaphthodioxepins 223 were obtained from arylsulfonylalkynes via Michael reaction. The procedure engages NaH-supported reaction of 1,1 -binaphthalene-2,2 -diol 222 with 220 (Ar = phenyl, tolyl). The procedure can also be performed using (Z)- or (ft)-l-chloro-2-phenylsulfonylethylene and bis(phenylsulfonyl)ethylene, respectively, instead of arylsulfonylalkynes (Scheme 64) <1996SL1481>. 

The first investigations on iron-catalyzed Michael reactions utilized Fe(acac)3 as catalyst. However, this metal complex is itself catalytically almost inactive. Yields of only up to 63% could be achieved, if BF3OEt2 is used as a co-catalyst [55], Polystyrene-bound Fe(acac)3 catalysts were also reported to give yields up to 63% [56], FeCl3 was used as a co-catalyst for clay-supported Ni(II). Yields achieved with this heterogeneous system ranged from 40 to 98% [57]. The double Michael addition of acrylonitrile to ethyl cyanoacetate is smoothly catalyzed by a complex generated from [Fe(N2) (depe)2] [depe = l,2-bis(diethylphosphano)ethane]. At 23 °C and after 36h, an 88% yield is obtained with 1 mol% of this Fe(0) catalyst [58]. 

Solid-phase synthesis is of importance in combinatorial chemistry. As already mentioned RuH2(PPh3)4 catalyst can be used as an alternative to the conventional Lewis acid or base catalyst. When one uses polymer-supported cyanoacetate 37, which can be readily obtained from the commercially available polystyrene Wang resin and cyanoacetic acid, the ruthenium-catalyzed Knoevenagel and Michael reactions can be performed successively [27]. The effectiveness of this reaction is demonstrated by the sequential four-component reaction on solid phase as shown in Scheme 11 [27]. The ruthenium-catalyzed condensation of 37 with propanal and subsequent addition of diethyl malonate and methyl vinyl ketone in TH F at 50 °C gave the adduct 40 diastereoselectively in 40 % yield (de= 90 10). 

Another impressive example of the transition metal-catalyzed Michael reaction was reported by Sawamura and Ito in 1992 (Scheme 6) [7]. a-Methylcyanoacetate was treated with enones using 1 mol% Rh-TRAP (12) complex, and the corresponding adduct 13 was formed in up to 93 % ee. For this reaction, the trans-coordination mode of the chiral diphosphine 12 was essential for high asymmetric induction. It was proposed that coordination of the nitrile group to Rh, then oxidative addition of the active methine C-H bond gave not the a-C-bound enolate, but the nitrile-coordinating enolate 14, which was considered to be a reactive intermediate. The unique structure of this enolate was supported by X-ray analysis of a similar achiral Ru-cyanoacetate complex [8]. 

With the exception of Yb(OTf)3 3H2O, indium salts and Bronsted acids, there are several metal-based Lewis acid catalysts available for these Michael reactions, such as a CeCl3 7H20-NaI combination supported on... 

Polymer-supported quaternary ammonium hydroxides have been used to catalyse Michael reactions between various alkyl methacrylates, acrylonitrile, and methyl vinyl ketone as acceptors and nitro or keto derivatives as donors.[116,117]... 

Another interesting feature of polymer-supported catalysts containing quaternary ammonium salts involves the development of enantioselective catalysis using salts derived from cinchonia or ephedra alkaloids.11341 The first application of such chiral supported catalysts in the Michael reaction between methyl 1-oxoindan-2-carboxylate and methyl vinyl ketone revealed a high chemical yield in condensation product (60-100 %) although the enantioselectivities were only moderate (ee <27 %). 

Hodge, P., Khoshdel, E. and Waterhouse, J. Michael reactions catalyzed by polymer-supported quaternary ammonium-salts derived from cinchona and ephedra alkaloids, J. Chem. Soc., Perkin Trans. 1, 1983, 2205-2209. 

Amberlyst 21 (59) and solid-supported cinchonidine (60) have been used to catalyze the Michael reaction between 61 and methyl vinyl ketone 62 in flow (Scheme 4.80). The reactions using Amberlyst 21 were run at 50 °C and required a residence time of 6h (120 pl/min) for the reaction to reach completion (99% yield). The asymmetric reactions using 60 under the same conditions formed 63 in 97% yield with 52% ee of the S-isomer the system could be run continuously for 72 h without any observed loss of activity [181]. 

Schiff s base (Illb), which is then degraded by a reverse Michael reaction to the protonated 3-methyleneindolenine (IIIc). Addition of ammonia then yields 3-aminomethylindole, which on methylation affords gramine (III). This attractive hypothesis finds support in the recent isolation from barley seedlings of both 3-aminomethylindole and 3-methyl-aminomethylindole (57b). It is also supported by the demonstration that 3-aminomethylindole can be methylated to 3-methylaminomethylindole... 

For solid-phase synthesis of 26.4 (Figure 15.26), compound 26.1 was immobilized on the resin as for the previous example (loading 86%, 26.2). The free hydroxyl derivative obtained after the acetonide removal was subjected to crucial hetero-Michael reaction. The use of NaH as a base at room temperature provided the expected product 26.3. After cleavage from the support, the crude sample was purified giving product 26.4 (25% overall yield in four steps), which was further assigned by NMR. It was interesting to note that this unusual regio- and stereoselective hetero-Michael reaction worked in a similar manner as in solution synthesis. For comparison purposes, compound 26.5 was also synthesized in solution in a similar manner. 

Ni(II)(OAc)2bpy and Co(II)(OAc)2bpy catalyze the Michael addition of nitro-methane, malononitrile, and aniline to a,j8-unsaturated ketones, methyl acrylate, and acrylonitrile in DMF under neutral conditions [116]. FeCls 6H2O is a highly efficient catalyst of Michael reaction of 1,3-dicarbonyl compounds with a,/3-unsaturated ketones under mild and neutral conditions (Sch. 24) [117]. There is literature precedent for this reaction with dual catalysis Ni(II) immobilized on a clay support and FeCl3 to activate the enone [118]. The mechanism proposed for the single-center catalysis involves coordination of the enone to a diketonato complex [119]. The chemo-... 

Rare earth metal triflates are recognized as a very efficient Lewis acid catalysts of several reactions including the aldol reaction, the Michael reaction, allylation, the Diels-Alder reaction, the Friedel-Crafts reaction, and glycosylation [110]. A polymer-sup-ported scandium catalyst has been developed and used for quinoline library synthesis (Sch. 8) [111], because lanthanide triflates were known to be effective in the synthesis of quinolines from A-arylimines [112,113]. This catalyst (103) was readily prepared from poly(acrylonitrile) 100 by chemical modification. A variety of combinations of aldehydes, amines, and olefins are possible in this reaction. Use of the polymer-supported catalyst has several advantages in quinoline library construction. 

Oxidations. Glycol and microwave irradiatiim same method seems to I titanium/tartaric acid caul hydrogen peroxide as the 1 A percarboxylic acid, orthosilicate to aqueous eti is hydrolyzed and treated 1 Miscellaneous reactit Friedel-Crafls reaction derivatization that introd catalyzing Michael react supported on silica gel by... 

Miscellaneous reactions. Mediated by grounded FeClj and silica gel the Friedel-Crafts reaction of arenes with ArCCl, provides benzophenones. After derivatization that introduces dimethylaminopropyl pendants the silica is useful for catalyzing Michael reactions. Alcohols are attached to carboxylic acids which are supported on silica gel by esterification. ... 

Michael reactions. Many commonly known conjugate additions can be carried out in water" in the presence of Yb(OTf)j, sometimes also at high pressure and sometimes on silica gel supports. ... 

A similar approach has been examined by using polymer-supported ALB 91 (Scheme 3.25). When this polymeric chiral ALB catalyst was used for the asymmetric Michael reaction, the corresponding chiral adduct was obtained in 91% yield with 96% ee [48]. 

A silica-supported phenoxide gave a 99% yield in the Michael reaction (6.25).87... 

Asymmetric synthesis of P-phosphono-malonates via K0H/Fe203 catalyzed phospha-Michael reaction to Knoevenagel acceptors has been achieved by Enders and Tedeschi [57]. The reaction did not proceed when only KOH was used as a catalyst Fe203 was the best diastereoselective support among the other supports tested, A1203, ZnO, Cu20, Mn02 and MgO. 

Finally, binary cesium-lanthanum oxides supported on MCM-41 have been tested in the liquid phase as catalysts of the Knoevenagel and Michael reactions... 

There are also examples of enantioselective Michael reactions on helerogcni/ed chiral amines (cinchonidine and cinchonine) (Figure 20d) [I65. Further examples ol Michael additions use nitromcthane, maloniirile. diethyl malonaie. cyanoaceianiide or thiols as donors and methyl vinyl ketone, methyl aciylaic and simple and substituted chalconcs as acceptors 70. 81. 114. 245. 265, 266). As for the catalysts, they can be cation-promoted Ba(OM) [70], hydroxyapatite 1245]. supported KF (114). alkaline carbiuiaies (I02. hydrolalciies (2(>51... 

In this nucleophilic Michael reaction, the supported catalyst 132 was first dissolved in heptane. Then an equal volume of an ethanol solution of the substrates was added. The resultant reaction occurred in a homogeneous mixture... 

Fetterly, B.M., Jana, N.K. and Verkade, J.G. (2006) [HP(HNCH2CH2)3N]N03 an efficient homogeneous and solid-supported promoter for aza and thia-Michael reactions and for Strecker reactions. Tetrahedron, 62, 440-456. 

Wannapom, D. and Ishikawa, T. (2005) Polymer-supported and polymeric chiral guanidines preparation and application to the asymmetric Michael reaction of iminoacetate with methyl vinyl ketone. Molecular Diversity, 9, 321-331. 

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